Phenyl substituted-2,4,6,8-nonatetraenoic acid

ABSTRACT

The compounds 9-phenyl-3,7-dimethyl-2,4,6,8 nonatetraenoic acids wherein the phenyl group is substituted with an alkyl, aminoalkyl, hydroxyalkyl, alkoxy, hydroxyalkylamino, and a hydroxy alkoxy group, and derivatives thereof which are used as disease modifying anti-rheumatic agents and as immunosuppressants.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 635,100 filed July 27, 1984, and now abandoned--Aig Coffey,Lovey and Rosenberger.

SUMMARY OF THE INVENTION

In accordance with this invention, it has been discovered that compoundsof the formula: ##STR1## and compounds of the formula ##STR2## wherein nis an integer selected from 6 or 7; R₁ is hydrogen, loweralkyl,chlorine, fluorine or trifluoromethoxy; R₂ is hydrogen, lower alkoxy,trifluoromethylloweralkoxy, hydroxy, lower alkyl, chlorine,trifluoromethyl, or fluorine; R₃ is hydrogen, loweralkyl, chlorine orfluorine; R₄ is alkyl containing from 4 to 10 carbon atoms; X is##STR3## and R₇, R₈ R₉ and R₁₀ are individually lower alkyl or hydrogen;

and salts thereof where R₉ is hydrogen, are useful in treatingrheumatoid arthritis as well as related disorders and diseases resultingfrom immune hyperactivity.

In the past retinoids which have been active as disease modifiers fortreating rheumatoid arthritis also tend to display the toxic symptoms ofhypervitaminosis at dosages which show disease modifying effects. Inaccordance with this invention, the compounds of formula I and IIpossess this disease modifying effects while being relatively non-toxic.The compounds of formula I and II also act as immunosuppressant agents.

DETAILED DESCRIPTION

FIGS. 1, 2, 3, 4, 5, 6 and 7 represents schematic process steps forpreparing the compounds of formula I and II above.

In the compounds of this invention the term "halogen" includes all fourhalogens, i.e. chlorine, bromine, iodine and fluorine with chlorine andbromine being preferred. The term "lower alkyl" as used hereindesignates both straight and branched chain lower alkyl group consistingfrom 1 to 7 carbon atoms. Among the preferred lower alkyl groups aremethyl, ethyl, isopropyl, n-butyl, etc., with methyl and ethyl beingespecially preferred. The term "lower alkoxy" designates lower alkoxygroups containing from 1 to 7 carbon atoms such as methoxy, ethoxy,isopropoxy, isobutyoxy, etc. The term trifluoromethyl lower alkoxydesignates a trifluoromethyl substituted lower alkoxy substituent wherelower alkoxy is defined as above. The term alkylidene designates aaliphatic saturated hydrocarbon group where the terminal carbon atoms isdivalent.

The term "aryl" designates mononuclear aromatic hydrocarbon groups whichcan be unsubstituted or substituted in one or more positions with alower alkyl groups, such as phenyl or tolyl, etc. and polynucleararomatic groups which can be unsubstituted or substituted in one or morepositions with a lower alkyl group and as napthyl, phenanthryl oranthryl. The preferred aryl group is phenyl.

In one of the embodiments of the compounds of Formula I, R₇ and R₈ arelower alkyl preferably methyl and R₄ is preferably --(CH₂)y H with ybeing either 6 to 9 with 9 being especially preferred. In thisembodiment of the invention, R₁, R₂ and R₃ are preferably hydrogen or R₁and R₃ can be hydrogen and R₂ can be lower alkoxy such as methoxy orethoxy. On the other hand in this embodiment R₂ and R₃ can be hydrogenwith R₁ being chlorine or fluorine or R₁ and R₂ can be hydrogen with R₃being chlorine or fluorine.

In one embodiment of the compound of formula II, R₈ and R₇ are loweralkyl, preferably methyl. In this embodiment of the compound of formulaII, R₁, R₂ and R₃ are hydrogen, or R₁ is chlorine or fluorine with R₂and R₃ being hydrogen. On the other hand in this embodiment of thecompound of formula II, R₁ and R₃ are hydrogen and R₂ is lower alkoxypreferably methoxy or ethoxy. Also preferred are those compounds of thisembodiment of the compound of formula II where R₁ and R₂ are hydrogenand R₃ is chlorine or fluorine.

Also included in this invention are salts of the compound of formulae Iand II above with pharmaceutically acceptable, non-toxic, inorganic ororganic bases, e.g. alkali metal and alkaline earth metal salts. Amongthe preferred salts are the sodium, potassium, magnesium or calciumsalts, as well as salts with ammonia or suitable non-toxic amines, suchas lower alkyl amines, for example triethylamine, hydroxy-loweralkylamines, for example 2-hydroxyethylamine, bis-(1-hydroxyethyl)amineor tris-(2-hydroxyethyl)-amine, cycloalkylamines, for exampledicyclohexylamine, or benzylamines, for exampleN,N'-dibenzyl-ethylenediamine, and dibenzylamine. These salts can beprepared by treating the compounds of formulae I and II, where R₉ ishydrogen with inorganic or organic bases by conventional means wellknown in the art.

The compounds of formula I and II as well as salts thereof are effectiveas disease modifiers for treating rheumatoid arthritis as well asrelated disorders such as osteo-arthritis. The compounds of formula Iand II also have activity as immunosuppressants.

The compounds of formulae I and II and salts thereof can be utilized totreat patients suffering from rheumatoid arthritis and relateddisorders. In such cases, the compounds modify the effects of thesediseases by reducing destruction of the bone joints caused by thisdisease as well as reducing inflammation, heat and pain of the bonejoints which results from rheumatoid arthritis and related disorders.The compounds of formulae I and II and salts thereof are also useful fortreating diseases resulting from immune hyperactivity such astransplantation autoimmunity, autoimmune disease and graft versus hostdisease. The unexpected lack of toxicity of the compounds of thisinvention can be seen by the fact that the compound(all-E)-9-[2-(nonyloxy)-phenyl]-3,7-dimethyl-2,4-6,8-nonatetraenoic acidhas a LD₅₀ in mice of greater than 1,000 mg/kg both i.p. and p.o.

That the compounds of this invention are effective anti-arthritic agentscan be seen from the results obtained when these compounds areadministered to rats in accordance with the chronic adjuvant arthritistest system disclosed in Billingham and Davies "Handbook of ExperimentalPharmacology" (editors J. R. Vane and S. H. Ferreira) Vol. 50/II, pg.108-144, Springer-Verlag, Berlin, 1979).

In this procedure, adjuvant arthritis was induced by the subplantarinjection on day 0 of 0.05 ml of adjuvant [a suspension of heat-killed,dessicated Mycobacterium butyricum, 0.5% (w/v), in heavy mineral oilcontaining 0.2% digitonin] into the right hind paw of male Charles RiverLewis rats (120-140 g) that were housed individually and given food andwater ad lib. Paw volumes (both hind paws) were measured immediatelyafter injection of the adjuvant. Paw Volumes were also measured, tofollow the development of inflammation-induced swelling in the arthriticpaws, at intervals of 3 to 7 days by immersion of the paw to the levelof the lateral malleolus in a mercury plethysmograph.

Drugs were administered once a day (starting on the day of adjuvantinjection) by incubation using Tween 80 (polyoxyethylene sorbitanmono-oleate) at a dose of 0.25 ml/100 g body weight as the vehicle.Arthritic control rats received daily doses of the vehicle only. On day23-25, the rats were sacrificed, plasma collected and plasma fibrinogenlevels determined (ammonium sulfate turbidimetric method) as describedby Exner et al., Amer. J. Clin Path, 71:521-527 (1979).Anti-inflammatory activity of the test drugs were determined bycomparing the extent of paw swelling (paw volume on a particular day,i.e. day four to day twenty-five, minus the paw volume on day 0) indrug-treated arthritic rats with the extent of paw swelling in thevehicle-treated arthritic rats. Drug induced decreases in the level ofplasma fibrinogen, an acute phase protein that is elevated in the plasmaof rats with adjuvant-induced arthritis, were also used to quantitatethe anti-inflammatory activity.

The results of various compounds of this invention when compared toIndomethacin and 13-cis-vitamin A acid are given in the following table(TABLE I).

                                      TABLE I                                     __________________________________________________________________________                                          % Reduction in                                                                Paw Volume On                                                                          Plasma fibrinogen                                              Oral Dose                                                                           day 23   % change Body Weight           STRUCTURE                       μMol/Kg                                                                          Right                                                                              Left                                                                              (reduction)                                                                            Gain                  __________________________________________________________________________                                                            (g)                   Vehicle                         --    --   --  --       28-31                 Indomethacine                    3    -66  -67 -30      +46                    ##STR4##                       60    -33  -49 -18       -7                    ##STR5##                       76    -43  -58 -55      +27                    ##STR6##                       75    -27  -24 -21      +27                    ##STR7##                       75    -53  -53          +24                    ##STR8##                       75    -29  -32          +35                    ##STR9##                       96    -37  -49 -35      +27                    ##STR10##                      75    -56  -68 -51      +46                   __________________________________________________________________________

In the above Table I the percent reduction in paw volume demonstratesthe effectiveness of compounds of this invention to reduce swellingcaused by adjuvant arthritis. As seen from the results in this Table,the compounds of this invention effectively reduce the swelling causedby the adjuvant. Furthermore the compounds of this invention wereeffective in reducing the plasma fibrinogen generally associated withrheumatoid arthritis. Furthermore as seen from the weight gain of theanimals, the compounds of this invention at the dosage tested producedno substantial reduction in the weight gain of the animals. Thisindicates the lack of toxicity exhibited by the compounds of thisinvention.

The compounds of formulae I and II and their pharmaceutically acceptablesalts can be used in a variety of pharmaceutical preparations. In thesepreparations, these compounds are administrable in the form of oral unitdosage forms such as tablets, pills, powders, capsules, as well as insuch forms as injectables, solutions, suppositories, emulsions,dispersions, and in other suitable forms. The pharmaceuticalpreparations which contain the compounds of formulae I and II areconveniently formed by admixing with a non-toxic pharmaceutical organiccarrier or a non-toxic pharmaceutical inorganic carrier. Typical ofpharmaceutically acceptable carriers are, for example, water, gelatin,lactose, starches, magnesium stearate, talc, vegetable oils,polyalkylene glycols, petroleum jelly and other conventionally employedpharmaceutically acceptable carriers. The pharmaceutical preparationsmay also contain non-toxic auxiliary substances such as emulsifying,preserving and wetting agents and the like, as for example, sorbitanmonolaurate, triethanol amine oleate, polyoxyethylene sorbitan, dioctylsodium sulfosuccinate and the like.

The daily dose administered for the compounds will, of course, vary withthe particular novel compound employed, the chosen route ofadministration and the size of the recipient. The dosage administered isnot subject to definite bounds but it will usually be in effectiveamounts of the pharmacologically function of the compounds of thisinvention. Representative of a typical method for administering thecompounds of formulae I and II or their salts is by oral administration.By this route, the compounds of formulae I and II or their salts can beadministered at a dosage of 0.5 mg/kg per day p.o. to 100 mg/kg per dayp.o. Preferably these compounds can be administered daily to patients inunit oral dosage forms at daily dosages of from 1 to 30 mg/kg of bodyweight, with dosages of from 1 to 10 mg/kg being especially preferred.

The compound of formula I where X is --O-- i.e. compounds of theformula: ##STR11## wherein R₁, R₂, R₃, R₄, R₅, R₇ and R₈ are as above,

and compounds of the formula II where X is --O-- i.e. compounds of theformula ##STR12## wherein n, R₁, R₂, R₃, R₇, and R₈ are as above, can beprepared from compounds of the formula ##STR13## wherein R₁, R₂ and R₃are as above, via the reaction scheme in FIG. 1.

In the reaction scheme of FIG. 1, R₁₁ is both --CH₂ --(CH₂)_(n) --CH₂ OHand R₄. Also in this reaction Scheme n, R₁, R₂, R₃, R₇ and R₈ are asabove and R'₉ is lower alkyl, Z is a leaving group; Y is aryl preferablyphenyl; Z' is halo.

The compound of formula III is converted to the compound of formula IVvia reaction step (a) by reducing the aldehyde group to the alcohol.This reaction is carried out utilizing a conventional reducing agentwhich converts aldehydes to alcohols. Any conventional reducing agentfor this purpose can be utilized in the reaction of step (a). Incarrying out this reaction it is generally preferred to utilize analkali metal borohydride such as sodium borohydride as the reducingagent. Any of the conditions conventional in such reduction reactionscan be utilized to carry out the reaction of step (a). If R₂ is hydroxyit is generally preferred to protect the hydroxy designated by R₂ duringthe reduction of the compound of formula III and its subsequentconversion to the compound of formula II-A. Any conventionalhydrolizable hydroxy protecting group such as a lower alkanoyl group maybe utilized to protect the hydroxy group when R₂ is hydroxy. This esterprotecting group can be cleaved by conventional ester hydrolysis afterthe formation of the Wittig salts of formulae XIII and XVI or after theformation of the ether of formula X.

The compound of formula IV is converted to the compound of formula VIvia reaction step (b) by treating the compound of formula IV with atriarylphosphine hydrohalide. In this manner the phosphonium salt offormula VI is produced. Any conventional method of reacting an allylicalcohol with a triarylphosphine hydrohalide can be used to carry outthis reaction. The phosphonium salt of formula VI is reacted via aWittig reaction with the compound of formula VII in step (c) to form thecompound of formula VIII. Any of the conditions conventionally used inWittig reactions can be utilized to carry out the reaction of step (c).

On the other hand the compound of formula III may be directly convertedto the compound of formula VIII via the reaction with the phosphoniumsalt of the compound of formula IX as in reaction step (e). The reactionof the phosphonium salt of formula IX with the compound of formula IIIto produce the compound of formula VIII is carried out utilizing thesame conditions as described in connection with reaction step (c).

The compound of formula VIII is converted to the compound of formula Xby etherifying or alkylating the compound of formula VIII with acompound of formula V as in reaction step (d). In the compound offormula V, Z can be any conventional leaving group such as mesyloxy,tosyloxy or a halide. Any conventional method of etherification of ahydroxy group though reaction with a halide or a leaving group can beutilized to carry out the reaction of step (d).

In accordance with another embodiment of this invention the compound offormula X, where when R₂ is hydroxy, the hydroxy group is protected viaa hydrolizable ester, can be produced from the compound of the formulaIII by alkylation or etherification of the compound of formula III withthe compound of formula V to produce the compound of XI. This reactionis carried by alkylating the compound of formula III with the compoundof formula V as in step (d). In the reaction of steps (f) and (d) whereR₁₁ is a hydroxy alkyl group, the hydroxy contained in R₁₁ need not beprotected. This is true since under the conditions used in this reactionstep, the compound of formula V will react with either the compound offormula III or the compound of formula VIII to produce the compound offormula XI or the compound of formula X without the necessity forprotecting the hydroxy group contained on the alkyl chain. Alkylation oretherification will occur directly with the phenyl hydroxy moiety oneither the compound of formula III or the compound of formula VIII andthere will be little, if any reaction with the hydroxy group containedon the alkyl chain designated by R₁₁. The compound of formula XI isconverted to the compound of formula XII, via reaction step (g) byreduction. The same conditions described in connection with reactionstep (a) can be utilized to convert the compound of formula XI to thecompound of formula XII.

The compound of formula XII is converted, via reaction step (h), to thecompound of formula XIII by treating the compound of formula XII with atriarylphosphine hydrohalide in the manner described hereinbefore inconnection with step (b). The compound of formula XIII is converted tothe compound of formula X by reacting the compound of formula XIII withthe compound of formula VII via reaction step (i). This reaction step iscarried out in the same manner as described hereinbefore in connectionwith reaction step (c).

In accordance with another embodiment of this invention the compound offormula X is produced by first converting the compound of formula XI tothe compound of formula XIV. The compound of formula XI is converted tothe compound of formula XIV by aldol condensation with the compound offormula XX. Any conventional method of aldol condensation can beutilized to react the compound of formula XI with the compound offormula XX to form the compound of formula XIV. In the next step thecompound of formula XIV is condensed via either a Grignard reaction withvinyl magnesium halide or a lithium condensation reaction with vinyllithium to produce the compound of formula XV. The reaction of step (k)can be carried out by utilizing any of the conditions conventional inlithium condensations or Grignard condensation reactions. The compoundof formula XV is converted to the compound of formula XVI by reactingthe compound of formula XV with a triarylphosphine hydrohalide in themanner described hereinbefore in connection with the reaction of step(b). The compound of formula XVI is thereafter converted to the compoundof formula X, via reaction step (m), by reaction with the compound offormula XVII. The reaction of step (m) is carried out utilizing astandard Wittig reaction as described in connection with the reaction ofstep (c). The compound of formula XVI by the reaction with the compoundof formula XVII produces the compound of formula X. The compound offormula X is the compound of formula I-A and II-A where R₅ is anesterified carboxy group. The compound of formula X can be converted tothe free acid i.e. the compound of formula I-A and II-A where R₅ is COOHby ester hydrolysis. Any conventional method of ester hydrolysis willproduce the compound of the formula I-A and II-A where R₅ is COOH.

The compound of formula I where X is ##STR14## i.e. compounds of theformula ##STR15## wherein R₁, R₂, R₃, R₄, R₇, R₈, R₉ and R₁₀, are asabove,

and compounds of the formula II where X is ##STR16## i.e. compounds ofthe formula: ##STR17## wherein n, R₁, R₂, R₃, R₈, R₇, R₉ and R₁₀ are asabove;

are prepared from the compound of the formula ##STR18## wherein R₁, R₂and R₃ are as above via the reaction scheme in FIG. 2.

In FIG. 2, R₁, R₂, R₃, R₇, R₈, R₉ ', R₁₁, Z' and Y are as above. In FIG.2, R₁₃ is the same as R₄ however it is an alkyl group with one lesscarbon than the alkyl group contained by R₄. Therefore R₁₃ is an alkylgroup containing from 3 to 9 carbon atoms. On the other hand, R₁₃ canalso be --CH₂ (CH₂)_(m) CH₂ OH where m is a number one less than n.Therefore R₁₃ is --CH₂ --(CH₂)_(m) --CH₂ OH where m is an integer offrom 5 to 6. In FIG. 2, R₁₀ is hydrogen or lower alkyl containing from 1to 7 carbon atoms and R₁₀ ' is a lower alkyl group containing from 1 to7 carbon atoms. In this embodiment R₁₀ " is a lower alkyl group havingone carbon atoms less the alkyl group designated by R₁₀ '.

In FIG. 2 the compound of formula XXII is reacted with acid chloride offormula XIX where Z' is halogen to produce the compound of formula XXIIIwhich is later converted either to the compound of formula XXVI or thecompound of XXXI. Where R₁₃ in the compound of formula XIX is --CH₂--(CH₂)_(m) CH₂ OH where m is an integer of from 5 to 6 carbon atoms,the presence of the hydroxy group on the substituent of R₁₃ will noteffect the reaction to produce the compound of formula XXVI or thecompound of formula XXXI. It has been found that this hydroxy groupremains unaffected throughout the series of reactions set forth in FIG.2.

On the other hand this hydroxy group can be protected by means offorming a hydrolyzable ether functional group which protects the hydroxygroup throughout these reactions. Any conventional ether protectinggroup can be utilized to protect the hydroxy group throughout thesereactions. Among the preferred ether protecting groups, are included:tetrahydropyranyloxy, t-butoxy, triloweralkylsilyloxy i.e.trimethylsilyloxy, etc. Any conventional ether protecting group can beutilized to protect the terminal hydroxy group which may be present asR₁₃. On the other hand, the reactions set forth in FIG. 2 can be carriedout without any protection of the terminal hydroxy group.

In the first step of the reaction, the compound of formula XXII isreacted with the compound of formula XIX to produce the compound offormula XXIII. Any conventional method of condensing an amine with anacid halide can be utilized to carry out this reaction. In the next stepthe compound of formula XXIII is converted to the compound of formulaXXIV, via reaction step (n), by treating the compound of formula XXIIIwith a reducing agent. Any conventional alkali metal aluminum hydridereducing agent can be utilized to carry out this reaction with thepreferred reducing agent being lithium aluminum hydride. Any of theconditions conventional in reducing with an alkali metal aluminumhydride reducing agent can be utilized to carry out this reaction.

The compound of formula XXIV can be converted to the compound of formulaXXVI via the intermediate XXV. In the first step of this procedure, step(o), the compound of formula XXIV is converted into the phosphonium saltof formula XXV by reaction with a triarylphosphine hydrohalide asdescribed hereinbefore in connection with the reaction of step (b). Thecompound of formula XXV is converted to the compound of formula XXVI viareaction step (p), by reaction with the aldehyde of formula VII. (SeeFIG. 1). The reaction of step (p) to produce the compound of formulaXXVI is carried by a Wittig reaction in the same manner as described inreaction step (c) hereinbefore. The compound of formula XXVI where R₉ islower alkyl can, if desired, be converted into the free acid byconventional basic hydrolysis. Any conventional method of basichydrolysis to hydrolize esters can be utilized to convert the compoundof formula XXVI to the free acid. On the other hand, the compound offormula XXVI where R₁₁ contains a terminal hydroxy group etherified witha conventional ether protecting group can be converted into the freealcohol by acid hydrolysis. Any of the conventional methods ofhydrolyzing ethers can be utilized to carry out this reaction. The etherhydrolysis of the compound of formula XXVI can be carried out eitherbefore or after the acid hydrolysis used to hydrolize the esterprotecting R₉ '. On the other hand if R₁₁ in the compound of formula Xin FIG. 1 contains an etherified hydroxy group, the compound of formulaX can be hydrolyzed in the same manner as is the compound of formulaXXVI.

On the other hand, the compound of formula XXIV can be converted to thetertiary amine compound of formula XXXI. In this reaction, the compoundof formula XXIV is reacted, via reaction step (q), with the acid halideof formula XIX-A, to produce the compound of formula XXVII in the samemanner described hereinbefore in connection with the reaction to convertthe compound of formula XXII to the compound of formula XXIII.

The compound of formula XXVII is converted to the formula XXIX, viareaction step (r), by treating the compound of formula XXVII with alithium aluminum hydride reducing agent as described in connection withreaction of step (n).

In the next step of this reaction scheme, the compound of formula XXIXis converted to the compound of formula XXX, via reaction step (s), bytreating with a triarylphosphine hydrohalide. This reaction is carriedout in the same manner as described in connection with reaction step (b)described hereinbefore. The compound of formula XXX is converted to thecompound of formula XXXI, via reaction step (t), by reaction with thecompound of formula VII (FIG. 1). In carrying out the reaction of step(t) a Wittig reaction is utilized. The reaction of step (t) can becarried out in the same manner as described hereinbefore in connectionwith the reaction of step (c). The compound of formula XXXI where R₉ 'is a lower alkyl group can be converted, if desired, to thecorresponding compound of the formula XXXI containing the free acidgroup by basic hydrolysis. On the other hand, if R₁₁ contains a terminalhydroxy group protected through the formation of a hydrolizable ether,the compound of formula XXXI can be converted to the correspondingcompound where R₁₁ is a free hydroxy group by conventional etherhydrolysis. This ether hydrolysis can be carried out before or afterhydrolysis of the ester group denoted by R₉ '.

In the reaction scheme of FIG. 2, when R₂ is hydroxy, it is preferredthat this hydroxy group be protected via the formation of an esterprotecting group. The ester protecting group can be removed after theformation of the Wittig salts of formula XXX.

The compounds of formula I and II where X is ##STR19## where R₁₀ ishydrogen or lower alkyl have the formula: ##STR20## wherein n, R₁, R₂,R₃, R₄, R₅, R₇, R₈ and R₁₀, are as above

are prepared from a compound of the formula: ##STR21## wherein Z" isether bromo or iodo; R₁, R₂, and R₃ are as above; and R₁₀ is hydrogen orlower alkyl

as set forth in FIG. 3. In FIG. 3, R₁, R₂, R₃, R₇, R₈, R'₉, R₁₀, R₁₁,R₁₃, Y, Z', and Z" are as above.

In FIG. 3, the compound of formula XXXV is first reacted with thecompound of formula XXXIV via reaction step (u) to produce the compoundof formula XXXVI. This reaction. is carried out via a Wittig reaction.In the compound of formula XXXVI R₁₃ can be, if desired, --CH₂--(CH₂)_(m) --OH where the free hydroxy group can, if desired, beprotected through the formation of any of the aforementionedconventional ether groups. On the other hand it has been found that thisOH group can be a free hydroxy group and need not be protected by meansof an ether protecting group. In carrying out the reactions of FIG. 3this free hydroxy group is not affected by the reactions which convertthe compound of formula XXXVI to the compound of formula XXXXI. Howeverfor best yields it is generally preferred to protect this hydroxy groupvia the formation of a hydrolizable ether.

The reaction of step (u) is carried out via a Wittig reaction betweenthe compounds of formula XXXV and the compound of formula XXXIVutilizing the same reaction conditions as described hereinbelow inconnection with reaction step (c).

The compound of formula XXXVI can be converted to the compound offormula XXXVII via a reaction step (v) by hydrogenation. Anyconventional method of hydrogenation can be utilized to carry out thisreaction. Among the conventional methods of hydrogenation are includedtreating the compound of formula XXXVI, in an inert organic solventmedium, with hydrogen gas in the presence of a catalyst. Anyconventional hydrogenation catalyst can be utilized in carrying out thisreaction. Among the preferred catalysts are included palladium. Incarrying out this reaction any conventional inert organic solvent can beutilized. Furthermore, any of the conditions conventional in catalytichydrogenation can be utilized in reaction step (v).

In the next step of this reaction, the compound of formula XXXVII isconverted to the compound of formula XXXIX via reaction step (w), bytreating compound of formula XXXVII with formaldehyde or a formaldehydeliberating compound. In carrying out this reaction the compound offormula XXXVII is first metalated with an alkali metal alkyl e.g.n-butyllithium. Generally this reaction is carried out in an inertorganic solvent such as an ether solvent. Among the preferred solventsare diethyl ether and tetrahydrofuran. In carrying out this reactiontemperature and pressure are not critical. This reaction can be carriedout at room temperature and atmospheric pressure. If desired, higher andlower temperatures can be utilized. After treating the compound offormula XXXVIII with an alkali metal alkyl, formaldehyde or aformaldehyde liberating compound is added to the reaction medium. Anyconventional compound capable of liberating formaldehyde such asparaformaldehyde can be utilized in carrying out this reaction. Thisreaction is carried out in the same reaction medium and utilizing thesame conditions as the metalation of the compound of formula XXXVIII wascarried out.

The compound of formula XXXIX is converted to the compound of formulaXXXX, via reaction step (x), by treating the compound of formula XXXIXwith triarylphosphine hydrohalide. This reaction is carried out in thesame manner as described in connection with reaction step (b) asdescribed hereinbefore. The compound of formula XXXX is converted, viareaction step (y), to the compound of formula XXXXI by reaction with thecompound of formula VII. (See FIG. 1). This reaction of step (y) iscarried out via a Wittig reaction utilizing the same conditionsdescribed in connection with reaction step (c). The compound of formulaXXXXI may be converted to corresponding compound containing the freecarboxyl group instead of R₉ '. This reaction is carried out byconventional ester hydrolysis in the manner hereinbefore described. Anyconventional method of ester hydrolysis can be utilized. If R₁₁ containsterminal hydroxy group protected through the use of an ether protectinggroup, this ether group can be hydrolized to yield the free hydroxygroup by conventional ether hydrolysis such as by utilizing an aqueousinorganic acid. Any conventional method of ether hydrolysis can beutilized. The protected ether hydroxy group can be hydrolized eitherprior to or after hydrolysis of the ester group to form the free acid ofthe compound of formula XXXXI.

It if it desired to produce compounds of the formulae I and I-A where Yis ##STR22## the compound of formula XXXV in FIG. 3 is reacted, viareaction step (u), with the compound of formula XXXIV where R₁₃ is R₁₁to produce the compound of formula XXXVI where R₁₃ is R₁₁. This compoundof formula XXXVI where R₁₁ is R₁₃ is then subjected to the same seriesof reactions as the compound of formula XXXVI, i.e. the reaction steps(w), (x) and (y), to produce the compounds of formulae I and I-A where Xis ##STR23##

In the reaction scheme in FIG. 3 where R₂ in the compound of formulaXXXV is a hydroxy group, it is preferred to protect this hydroxy groupvia esterification with a lower alkanoic acid. This ester protectinggroup can be cleaved after formation of the Wittig salt of formula XXXX.

The compound of formula I and II where X is ##STR24## has the formula##STR25## wherein R₁, R₂, R₃, R₅, R₇, R₈, R₁₀ and R₁₁ are as above

can be prepared from a compound of the formula ##STR26## wherein R₁, R₂,R₃ and Z" as above by the reaction scheme of FIG. 4. In FIG. 4, R₁, R₂,R₃, R₇, R₈, R₁₀, R₉ ', Y and Z" are as above and R₁₅ is R₄ or --CH₂--(CH₂)_(n) --CH₂ OR₁₇ wherein R₁₇ taken together with its attachedoxygen atom forms a hydrolizable ether group such as tetrahydropyranylas well as the ether groups mentioned hereinbefore and n is as above.

The compound of formula L is converted to the compound of formula LI byreaction with the alkali metal alkoxide of formula L-A. This reaction iscarried out by reacting the compound of formula L with the compound offormula L-A utilizing the conditions conventional in reacting an alkalimetal alkoxide with a halide.

In the step, the compound of formula LI is converted to the compound offormula LII by first treating the compound of formula LI with an alkyllithium such as n-butyl lithium to metalate the compound of formula LI.The metalated compound of formula LI is thereafter reacted withformaldehyde or a formaldehyde liberating compound. In converting thecompound of formula LI to the compound of formula LII, the same reactionconditions as described in connection with reaction step (w) are used inthis conversion. The compound of formula LII is converted to thephosphonium salt of formula LIII treating the compound of formula LIIwith a triarylphosphine hydrohalide in the manner set forth in reactionstep (b) above. The phosphonium salt of formula LIII is reacted via aWittig reaction with the compound of formula VII (see FIG. 1) to form acompound of formula LIV. This reaction to form the compound of formulaLIV is carried out in the same manner as described in connection withstep (c) hereinbefore.

When R₄ in the compound of formula LIV contains the protected hydroxysubstituent i.e., where R₁₇ taken together with its attached oxygen andforms the hydrolizable ether group, R₁₇ can be hydrolized to form thefree hydroxy compound by conventional methods for hydrolizing easilyremovable ether groups. Any conventional method for hydrolizing etherprotecting groups can be utilized. The conditions conventional forhydrolizing ether protecting groups will not affect the other ethergroup contained within the compound of formula LIV. The compound offormula LIV can be converted to the free acid by conventional esterhydrolysis.

If R₂ in the compounds of formulae L, LI, LII and LIII is hydroxy, it ispreferable that the hydroxy group be protected via a hydrolyzable estergroup such as lower alkanoyloxy. The hydrolyzable ester protecting groupcan be cleaved after forming the Wittig salt of formula LIII.

If desired, the double bonds within the compound of formula I and II atpositions 2-3, 4-5, 6-7 and 8-9 can be either in the cis or transconfiguration. On the other hand, these compounds can be a mixture ofthe various cis and trans isomers. In the compound of formula VII, thedouble bonds contained therein can be either in the cis or transconfiguration depending upon the desired stereo configuration of thedouble bonds within the compounds of formula I and II. The Wittigreaction carried out in producing the compounds of formula I and II suchas in steps (c), (e), (i), etc. produces the double bond at the 8-9position as a mixture of the 8-9 cis and trans isomers. These cis andtrans isomers can be separated by conventional means such as fractionalcrystallization, etc.

In addition, where the compounds of formula I and/or II have a doublebond in the trans configuration at the 2-3 position, this isomer can beconverted to the corresponding cis double bond with conventional methodsof isomerization known in the art. Among these procedures are includedtreating the compound of either formula I or II with iodine in an inertorganic solvent. Isomerization with iodine produces the compound offormula I with a 2-3 double bond in the cis position.

The compounds of formula I and II include all of its geometric isomersincluding mixtures of these geometric isomers.

The compound of formula XI where R₁ is fluoro is a new compound and canbe prepared from a compound of the formula ##STR27## where R₂ and R₃ areabove via the reaction scheme given of FIG. 5. In FIG. 5, R₂, R₃ and R₁₁are as above.

In FIG. 5, the compound of formula LV is alkylated by reaction with anallyl bromide. If the compound where R₂ is hydroxy is desired, thecompound of formula LV where the hydroxy group designated by R₂ isprotected by esterification is used as the starting material, i.e. thecompound of formula LV where R₂ is a protected hyroxy group. Anyconventional method of alkylating a hydroxy group with an allyl bromidecan be utilized to carry out the reaction of converting the compound ofLV to the compound of formula LVI. The compound of formula LVI isrearranged to the compound of formula LVI by heating the compound offormula LVI to a temperature from 190 degrees to 230 degrees centigrade.This rearrangement can take place without the use of any solvent or inthe presence of a high boiling hydrocarbon solvent. If R₃ is hydrogen,the compound of formula LVII is formed as a mixture with the isomer ofthe compound of formula LVII where the allyl group is para to thefluorine substituent on the benzyl ring. This isomer can be separated orutilized in the subsequent reactions and separated from the reactionmixture at a later stage.

The compound of formula LVII is thereafter converted to the compound offormula LVIII by reaction with the compound of formula V (FIG. 1) as setforth in reaction step (d) hereinbefore. In the next step of thisreaction scheme, the compound of formula LVIII is converted to thecompound of formula LIX by isomerization with a strong base such as analkali metal alkoxide in the presence of an inert organic solventpreferably potassium tertiary butoxide in dimethyl sulfoxide. Thecompound of formula LIX is converted to the compound of formula LX bytreating the compound of formula LIX with ozone gas. In carrying outthis reaction, temperatures of from minus 70 degrees centigrade to minus20 degrees centigrade are utilized. Furthermore this reaction is carriedout in an inert organic solvent. Any conventional inert organic solventcan be utilized, preferably halogenated hydrocarbons such as methylenechloride.

A compound of formula LX is the compound of formula XI wherein R₁ isfluoro. This compound can be converted to the compound of formula X inaccordance with the reaction scheme set forth in FIG. 1.

Where R₂ is hydroxy in the compound of formula III there are two hydroxygroups. Therefore, it is generally preferred to prepare the compound offormula XI where R₂ is a protected hydroxy group from a compound of theformula LXI as shown in FIG. 6. In this manner, compounds of formula I-Aand II-A can be prepared where R₂ is hydroxy and R₃ and R₁₁ are asabove. In FIG. 6, R₁ and R₁₅ taken with its attached oxygen atom, ishydroxy protected by a conventional hydrolyzable protecting grouppreferably a lower alkanoyl.

In FIG. 6, the compound of Formula LXI is converted to the compound offormula LXII utilizing the same reaction as described in connection withthe conversion of a compound of Formula LV to a compound of the FormulaLVI. (See FIG. 5) The compound of Formula LXII is next converted to acompound of Formula LXIII by utilizing the same procedure described inconnection with the conversion of the compound of Formula LVI to LVII.In the next steps the compound of Formula LXIII is converted to thecompound LXIV by the same procedure described in connection with step(g') in FIG. 5 and then to the compound of Formula LXV by the proceduredescribed in connection with step (h') in FIG. 5. The conversion ofbromobenzene compound of Formula LXV to the phenol compound of FormulaLXVI takes place by procedures well known in the art such as disclosedby Kidwell and Darling, Tetrahedron Letters, (1966) pgs. 531-535.

In the next step of preparing the intermediate of formula XI where R₂ isa protected hydroxy group, i.e. the compound of Formula XI-A, thehydroxy group is protected on the compound of formula LXVI throughesterification with any conventional hydrolyzable ester group to formthe compound of Formula LXVII where R₁₅ taken together is attachedoxygen forms a hydrolyzable ester group. Any conventional method ofesterifying a hydroxy groups with an organic acid such as a loweralkanoic acid containing from 1 to 7 carbon atoms can be used to preparethe compound of Formula LXVII. The compound of Formula XI-A is formedfrom the compound of Formula LXVII by the reaction describedhereinbefore with respect to the conversion of a compound of the FormulaLIX to LX (See FIG. 5).

In carrying out the conversion of a compound of Formula XI-A, to acompound of Formula XVII, as in FIG. 1, it is generally referred tohydrolyze the ester substituent which forms R₂ after the formation ofthe Wittig salt of Formula XIII or Formula XVI.

In accordance with another embodiment of this invention the compound offormula XI where R₁ is CF₃ (the compound of formula XI-B) can be formedby the reaction outlined in FIG. 7 from a compound of Formula LXX. Inthe first step of this reaction the compound of Formula LXX is convertedto a compound of Formula LXXI utilizing the same procedure describedhereinbefore in connection with the reaction, via step (d) where thecompound of Formula VIII is reacted with a compound of the Formula V toproduce a compound of the Formula X. In this reaction where R₂ is OH,alkylation occurs very slowly on the hydroxy group ortho to the CF₃group. Therefore, protection of this group may not be necessary sincealkylation proceeds preferably with the meta hydroxy group. Any mixturesof alkylated products obtained from this reaction can be separated byconventional separation procedures. The compound of formula LXXI isconverted to the compound of formula XII-B by conventional procedures offormylating a benzene ring such as by treatment with an alkyl lithiumand dimethylformamide.

The following examples are illustrative but limitative of the invention.In the examples the ether is diethylether and the solvents were removedin vacuo.

EXAMPLE 1 [[(2-(Nonyloxy)phenyl]methyl]triphenylphosphonium bromide

2-Hydroxybenzaldehyde (110 g), was alkylated by mixing this compoundwith 1-bromononane (180 g), anhydrous potassium carbonate anddimethylformamide (800 mL). This mixture was heated at 80° C. for 14hours. Hexane and water were then added and the hexane extract wasconcentrated and the residue was distilled to yield the2-nonyloxybenzaldehyde (210 g), bp 121° C. (0.3 mm Hg). A solution of2-nonyloxybenzaldehyde prepared above (100 g) in ethanol (1000 mL) at10° C. was reduced by treating with an excess of sodium borohydride (6g) and after stirring the mixture for a further 15-20 min. at roomtemperature, the compound 2-nonyloxybenzylalcohol was isolated byextraction into hexane. Removal of the hexane in vacuo yielded the crude2-nonyloxybenzylalcohol (98 g). The resulting 2-nonyloxybenzylalcoholwas added to a mixture of triphenylphosphine hydrobromide (144 g) inacetonitrile (500 mL) and the resultant solution was heated at refluxfor 14 hours. Removal of the solvents in vacuo and crystallization ofthe residue from a tetrahydrofuran/ethyl ether mixture gave the pure[[2-(nonyloxy)phenyl]methyl]triphenylphosphonium bromide (208 g).

EXAMPLE 2 [(2-Hydroxyphenyl)methyl]triphenylphosphonium bromide

2-Hydroxybenzyl alcohol was treated with triphenylphosphine hydrobromidein acetonitrile as described in Example 1 to yield[(2-Hydroxyphenyl)methyl]triphenylphosphonium bromide.

EXAMPLE 3 ALL(E)-9-(2-Hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester

A solution of [(2-hydroxyphenyl)methyl]triphenylphosphonium bromide (1mol) in tetrahydrofuran was converted to the ylide at -35° with asolution of n-butyllithium in hexane (2.1 mol equiv.) and then exposedto 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester (1 mol) andthen stirred at -70° for a further 15 min. Isolation of the organicproducts with a hexane/ethyl acetate mixture (4:1 parts by volume) anddilute mineral acid (2M aqueous HCl) gave the pureall(E)-9-(2-hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acidethyl ester (90% yield) after chromatography followed by crystallizationfrom a dichloromethane/hexane mixture.

EXAMPLE 4 ALL(E)-9-(2-Hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester

A mixture of 2-hydroxybenzaldehyde (0.5 mol),(7-carboxy-2,6-dimethyl-2,4,6-heptatrien-1-yl)triphenylphosphoniumbromide (0.6 mol) in 1,2-epoxybutane (750 mL) was heated at reflux for30 min. cooled, poured into an ether/hexane mixture (1:1 parts byvolume) filtered and concentrated. The residue was then crystallizedfrom a hexane/ether mixture to yieldall(E)-9-(2-hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acidethyl ester (38% yield), mp 143°-145°.

EXAMPLE 5(All-E)-9-[2-(Nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid

A solution of [[2-(nonyloxy)phenyl]methyl]triphenylphosphonium bromide(150 g) in tetrahydrofuran (1100 mL) was cooled to -50° C. to yield afine suspension of the solid salt. To this mixture was added a solutionof n-butyllithium in hexane (180 mL, a 1.6 molar) to yield a solution ofthe ylide. The mixture was then stirred a further 15 min at -40° C.,cooled to -70° and treated with 7-formyl-3-methyl-2,4,6-octatrienoicacid ethyl ester (65 g) dissolved in tetrahydrofuran (250 mL). Additionof hexane and aqueous methanol (40%) to the reaction mixture followed byconcentration of the hexane extract yieldedAll(E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acidethyl ester (64 g, 58% yield), mp 52°-53° C. This ester was thenhydrolized by forming a solution of this ester (70 g) in ethanol (1000mL). This solution was treated with aqueous potassium hydroxide (80 g in400 mL water) and heated at reflux for 1 h. Water and aqueous mineralacid was then added and the solids were extracted into chloroform.Concentration of this organic extract and crystallization of the residuefrom an ethyl acetate hexane mixture yieldedAll(E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid(38 g), mp 102°-103° C.

EXAMPLE 6(All-E)-9-[2-(Nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid

A mixture of sodium hydride (24 g, 50% by weight in mineral oil) anddimethylformamide (1000 mL) at 10° C. was treated withAll(E)-9-(2-hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acidethyl ester (0.4 equiv.). The resulting mixture was then stirred at roomtemperature until all hydrogen evolution had stopped to produce thesodium salt ofAll(E)-9-(2-hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acidethyl ester. A solution of 1-nonyl tosylate (0.5 equiv.) indimethylformamide (200 mL) was then added to this salt solution and thereaction mixture was stirred at 45° for 14 h. Hexane/water was thencarefully added and the hexane extract was concentrated and the residuewas purified by chromatography over silica gel. Crystallization fromhexane then yielded the pureAll(E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acidethyl ester. Hydrolysis of this ester as in Example 5 gave(All-E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid.

EXAMPLE 7 (All-E)-3,7-Dimethyl-9-[2-[(2,2-dimethyl-octyl)oxy]phenyl]-2,4,5,8-nonatetraenoic acid

2-Hydroxybenzaldehyde was condensed with 2,2-dimethyl-1-iodo octane toyield 2-(2,2-dimethyl octyloxy)benzaldehyde which was reduced to2-(2,2-dimethyl, octyloxy)benzyl alcohol and then converted to[[2-(2,2-dimethyloctyloxy)phenyl]methyl]triphenylphosphonium bromide asin Example 1. Condensation of this phosphonium bromide with7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described inExample 3 followed by hydrolysis, as in Example 5, gave the(All-E)-3,7-Dimethyl-9-[2-[(2,2-dimethyl-octyl)oxy]phenyl]-2,4,5,8-non-atetraenoicacid mp 113°-117° (from dichloromethane/hexane mixture).

EXAMPLE 8(All-E)-3,7-Dimethyl-9-[2-[(octyloxy)-methyl]phenyl]-2,4,6,8-nonatetraenoicacid

Lithium octanoate, prepared from octanol and n-butyllithium, in amixture of tetrahydrofuran/hexane dimethyl formamide was condensed with2-bromobenzyl bromide to yield 2(octyloxy)methylbromobenzene. Thismaterial was treated with n-butyllithium in ether/hexane mixture andsubsequently treated with paraformaldehyde to yield2-(octyloxy)methylbenzyl alcohol. This material was then treated withtriphenyl phosphonine bromide to yield[[2-[(octyloxy)-methyl]phenyl]methyl]triphenyl phosphonium bromide.Condensation of this material with 7-formyl-3-methyl-2,4,6-octatrienoicacid ethyl ester, as in Example 3, followed by hydrolysis, as in Example5, gave the(All-E)-3,7-Dimethyl-9-[2-[(octyloxy)-methyl]phenyl]-2,4,6,8-nonatetraenoicacid, mp 120°-121° (from dichloro methane/hexane mixture).

EXAMPLE 9(All-E)-9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid

2-chloro-6-hydroxy-benzaldehyde was alkylated with 1-bromononane as inExample 1 to give 2-chloro-6-nonyloxy benzaldehyde. Reduction withsodium borohydroxide as in Example 1 gave 2-chloro-6-nonyloxy benzylalcohol which on treatment with triphenylphosphine hydrobromide inacetonitrile as in Example 1 yielded[[2-chloro-6-nonyl-oxy]phenyl]methyl]triphenyl phosphonium bromide.Condensation with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl esteras described in Example 3 produced (AllE)-9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester. The ester was subjected to hydrolysis, as in Example5, to produce(All-E)-9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid mp 129°-131° (from ethyl acetate/hexane mixture).

EXAMPLE 10(All-E)-9-(5-Methoxy-2-nonyloxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid

5-Methoxy-2-hydroxybenzaldehyde was alkylated with nonylbromide andreduced with sodium borohydride, as in Example 1, to yield5-methoxy-2-nonyloxy-benzyl alcohol which on exposure totriphenylphosphine hydrobromide gave[(5-methoxy-2-nonyloxyphenyl)methyl]triphenyl phosphonium bromide.Condensation of this material with 7-formyl-3-methyl-2,4,6-octatrienoicacid ethyl ester, as in Example 3, followed by hydrolysis, as in Example5, gave(All-E)-9-(5-Methoxy-2-nonyloxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid mp 125°-126° (from methanol).

EXAMPLE 11All(E)-9-[2-(8-Hydroxyoctyl)oxy]phenyl-3,7-dimethyl-2,4,6,8-nonatetraenoicacid

The sodium salt ofAll(E)-9-(2-hydroxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acidethyl ester in dimethylformamide prepared as described in Example 6 wastreated with 1,8-dihydroxyoctane monotosylate as described previously inExample 6 and gaveAll(E)-9-[2-[8-hydroxyoctyl)oxy]phenyl-3,7-diethyl-2,4,6,8-nonatetraenoicacid ethyl ester after chromatography over silica gel. Hydrolysis as inExample 5 yieldedAll(E)-9-[2-[(8-hydroxy-octyl)oxy]phenyl]-3,7-dimethylphenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid, mp 122°-123° (from ethyl acetate).

EXAMPLE 12All(E)-[5-(2-Nonyloxyphenyl)-3-methyl-2,4-pentadienyl]triphenylphosphoniumbromide

2-(nonyloxy)benzaldehyde (62 g) dissolved in acetone (500 mL) wastreated with aqueous sodium hydroxide (100 mL, 1M) at room temperaturefor 18 h. Brine and ethyl acetate/hexane (1:1 parts by volume) was thenadded. Concentration of the organic phase followed by crystallizationfrom hexane gave 4-(2-nonyloxyphenyl)-3-butene-2-one (53 g).

A solution of 4-(2-nonyloxyphenyl)-3-butene-2-one (58 g) intetrahydrofuran (200 mL) was added to a solution of vinylmagnesiumbromide in tetrahydrofuran (200 mL, 1.6M diluted to 1L with moretetrahydrofuran) at -30° C. After complete addition, the mixture wasstirred at 0° C. for 30 min. quenched with saturated aqueous ammoniumchloride (100 mL) and ether (2L) and filtered free of solids.Concentration of the organic extract and purification by chromatographyover silica gel yielded(E)-5-(2-nonyloxyphenyl)-3-hydroxy-3-methyl-1,4-pentadiene (40 g) as anoil.

A solution of (E)-5-(2-nonyloxyphenyl)-3-hydroxy-3-methyl-1,4-pentadiene(66 g) in acetonitrile (250 mL) was added to a slurry oftriphenylphosphine hydrobromide (66 g) in more acetonitrile (300 mL) at10° C. After warming to room temperature, the mixture was stirred atthis temperature for 2 h to yield a solution. This solution was thenextracted with hexane (2×250 mL) and the acetonitrile layer wasconcentrated (ca. 400 mL) and cooled to -10°. The solids were filteredoff, washed with acetonitrile, hexane, and dried to give pureAll(E)-[5-(2-nonyloxyphenyl)-3-methyl-2,4-pentadienyl]triphenylphosphoniumbromide (21 g).

EXAMPLE 13

Starting with All(E)-[5-(2-nonyloxyphenyl)-3-methyl2,4-pentadienyl]triphenylphosphonium bromide and utilizing the procedureof Example 5, the ylide was reacted with 3-formyl-2-butenoic acid ethylester to yieldAll(E)-9-(2-nonyloxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acidafter purification by chromatography over silica gel and hydrolysis withaqueous ethanolic potassium hydroxide solution as in Example 5.

EXAMPLE 14(Z,E,E,E)-9-[2-(Nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid

All(E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl 2,4,6,8-nonatetraenoic acidethyl ester (10 g) was dissolved in hexane (200 mL) containing iodine(0.5 g) and stirred at room temperature for 30 min. The hexane waswashed free of iodine with an aqueous sodium thiosulfate solution (10%by weight), dried and concentrated to give a mixture of double bondisomers. Separation, by chromatography on silica gel, yielded pure(Z,E,E,E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester (1.5 g). Hydrolysis with aqueous ethanolic potassiumhydroxide at reflux gave the pure(Z,E,E,E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid: mp 135°-136° C.

EXAMPLE 15(E,E,E,Z)-9-[2-(Nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid

The mother liquor material resulting from the crystallization ofAll(E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acidethyl ester in Example 5 was a mixture containing various isomers.Purification by chromatography yielded an 80% pure ethyl ester whichafter hydrolysis as in Example 5 yielded pure(E,E,E,Z)-9[2(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid:mp 105°-109°.

EXAMPLE 16 2-Decyl-1-bromobenzene

Nonylmethyltriphenyl phosphonium bromide (0.1 mol) in tetrahydrofuran(200 mL) was converted to the ylide with n-Butyllithium (0.1 mol equiv;1.6M in hexane) at -10° C.

2-Bromobenzaldehyde (0.09 mol) was then added in tetrahydrofuran (25 mL)and after the mixture had been stirred for a further 30 min at 0° C.hexane and aqueous methanol (40:60) was added. The hexane extract wasconcentrated and the residue was distilled to yield2-(1-decenyl)-1-bromobenzene (90%).

This material was dissolved in hexane containing a palladium on carboncatalyst (10%) and hydrogenated at room temperature and pressure untilthe olefinic link was saturated. The solids were filtered off andremoval of the hexane and distillation of the residue gave pure2-decyl-1-bromobenzene (80%): bp 120° (0.001 mm Hg).

EXAMPLE 17 2-Decyl-1-hydroxymethylbenzene

2-Decyl-1-bromobenzene (0.1 mol) dissolved in ether (150 mL) was treatedwith n-butyllithium (0.11 eq. 1.6M in hexane) and the mixture wasstirred at room temperature for 2 hours.

Dry paraformaldehyde (0.2 mol eq) was then added and the mixture wasstirred for a further 18 h at room temperature.

Water and move ether was then added and the ether extracts were driedand concentrated. The residue after chromatography yielded pure2-decyl-1-hydroxy methyl benzene (75% yield).

EXAMPLE 18 All(E)-9-(Decylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid

2-Decyl-1-hydroxymethylbenzene was converted to the phosphonium saltwith triphenylphosphonium hydrobromide in acetonitrile by the procedureof Example 1. This salt was then exposed to n-butyllithium intetrahydrofuran as before and then treated with7-formyl-3-methyl-2,4,6-heptatrienoic acid methyl ester as before.

Purification of the crude condensation product by chromatography onsilica gel followed by basic hydrolysis yielded pureAll(E)-9-(decylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid: mp107°-108° (from hexane-ether).

EXAMPLE 19All(E)-9-(2-octylaminophenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acidethyl ester

2-Aminobenzyl alcohol (1 mol) was treated with octanoylchloride (2.2mol) in a mixture of dichloromethane-triethylamine at 0° C. After 30 minat 10° C. the mixture was washed with water and the ether was distilledoff. The crude residue was dissolved in tetrahydrofuran (2000 ml),treated with aqueous sodium hydroxide (1N, 1500 mL) and stirred at roomtemperature for 3 h.

Addition of water and ether yielded the crude hydroxymethyl octylamide.Purification by chromatography yielded the pure octyamide (85%).

This material (100 g) was dissolved in tetrahydrofuran (500 mL) andadded to a slurry of Lithium aluminum hydride (2 mol equiv) intetrahydrofuran (1000 mL). The mixture was then heated at reflux for 8 hcooled to 0° C. and quenched with aqueous sodium sulfate solution (100mL).

The solids were filtered off, the solvents were removed in vacuo and theresidue was purified by chromatography on silica gel to yield pure2-hydroxymethyl-N-octylamaline (75 g).

This material was dissolved in acetonitrile (300 mL) containingtriphenyl phosphine hydrobromide (1.1 eq) and the mixture was heated atreflux for 24 h and then concentrated. The residue was digested withether to give the phosphonium salt as a white solid.

This material was converted to the corresponding ylide withn-butyllithium (1.5 mol eq) and stirred at 0° for 1 h. Excess7-formyl-3-methyl-2,4,6-heptatrienoic acid ethyl ester (1.6 mol eq) wasthen added in tetrahydrofuran and the mixture was stirred at 10° C. for1 h.

Addition of hexane and aqueous methanol (2:3) and removal of the hexanein vacuo gave the crude coupled product. Purification by chromatographyon silica gel and crystallization from hexane gave pureALL(E)-9-(2-octyl amino phenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acidethyl ester (25%): mp 38°-40° C.

EXAMPLE 20 2-Fluoro-6-nonyloxybenzyl alcohol

A solution of 3-fluoro phenol (100 g) in dimethylformamide (1000 mL)containing potassium carbonate (165 g) was treated with allyl bromide(115 g) and heated at 80° for 18 hours.

Water and hexane were then added and the hexane extract was washed withaqueous sodium hydroxide solution (5%), saturated brine solution andconcentrated to yield the allyl ether (155 g). This material (134 g) washeated at 220° for 16 hours to yield a mixture of3-fluoro-2-(2-butenyl)phenol and 5-fluoro-2-(2-butenyl)phenol. Thismixture was dissolved in dimethyl formamide (2000 mL) containing1-bromononane (170 g) and potassium carbomate (150 g) and heated at 80°for 16 hours. Dilution with water and extraction with hexane yielded amixture of products on concentration. Distillation gave a mixture of3-[(2-fluoro-6-nonyloxy)phenyl]-butene and3-[(3-fluoro-2-nonyloxy)phenyl]-butene (186 g) bp. 120°-125° @ 0.1 mm.

This mixture of isomers (185 g) in dimethylsulfoxide (1000 mL)containing potassium tert-butoxide (1.5 g) was left at room temperaturefor 6 hours. Addition of water and extraction with hexane gave themixture of 1-[(2-fluoro-6-nonyloxy)phenyl]-butene and1-[(3-fluoro-2-nonyloxy)phenyl]butene.

This mixture of isomers (175 g) was dissolved in a mixture ofdichloromethane and methanol (9:1, 2000 mL) and exposed to a stream ofozone at -40° for 8 h. After this time the reaction mixture was pouredinto a mixture of water, hexane and dimethylsulfide (100 mL) and stirredat room temperature for 1 hour.

The hexane extract was washed (water), dried (MgSO₄), treated with moredimethyl sulfide (50 mL) and left at room temperature for 16 hours.

Removal of the solvents yielded the mixture of aldehydes2-fluoro-6-nonyloxybenzaldehyde and 4-fluoro-2-nonyloxy-benzaldehyde(155 g).

This mixture of aldehydes (150 g) in ethanol (2000 mL) was exposed tosodium borohydride (15 g) at 5° and then stirred at room temperature for30 min. Water (1500 mL), brine (500 mL) were then added and the mixtureof alcohols was extracted into hexane. Removal of the solvents andchromatography of the residue over silica gel (5% ethylacetate-hexanemixture) yielded pure 2-fluoro-6-nonyloxy-benzyl alcohol (76 g).

EXAMPLE 21(All-E)-9-2-Fluoro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid

A mixture of 2-fluoro-6-nonyloxybenzyl alcohol (19 g) andtriphenylphosphine hydrobromide (26 g) in acetonitrile (250 mL) washeated at reflux at 14 hours and then concentrated to dryness to yield[[(2-fluoro-6-nonyloxy)phenyl]methyl]triphenyl phosphonium bromide (42g). This phosphonium salt was dissolved in tetrahydrofuran (600 mL)cooled to -50° and treated with n-butyllithium (45 mL, 1.6M in hexane).After stirring a further 15 min at -50°7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester (8.4 g) was addedand the reaction mixture was warmed to room temperature and stirred fora further 15 min. Hexane ws then added and the mixture was washed withwater, 40% aqueous methanol and dried (MgSO₄). Concentration of thehexane extract and purification by chromatography (5% ether-hexane) gavethe pure trans isomer (11 g).

Crystallization from hexane-ethyl acetate gave(All-E)-9-[2-fluoro-6-(nonyloxy)-phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester (9.5 g).

A solution of the ester (6.5 g) in ethanol (150 mL) was treated with asolution of potassium hydroxide (7 g) in water (40 mL) and heated atreflux for 1 hour. The cooled reaction mixture was poured into coldaqueous hydrochloric acid and the acid was extracted into chloroform.Removal of the solvents and crystallization from hexane-ethyl acetategave pure(all-E)-9-[2-fluoro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid mp 107°-109°.

EXAMPLE 22

CAPSULE FORMULATIONS:

    ______________________________________                                        Item Ingredients   mg/capsule                                                                              mg/capsule                                                                            mg/capsule                               ______________________________________                                        1.   (All E)-9-    15          30        60                                        [2-(nonyloxy)                                                                 phenyl]-3,7-                                                                  dimethyl-2,4,6,                                                               8-nonatetraenoic                                                              acid                                                                     2.   Lactose       239         224       194                                  3.   Starch        30          30        30                                   4.   Talc          15          15        15                                   5.   Magnesium     1           1         1                                    Capsule fill weight                                                                          300    mg     300  mg   300  mg                                ______________________________________                                    

PROCEDURE:

(1) Mix items 1-3 in a suitable mixer.

(2) Add talc and magnesium stearate and mix for a short period of time.

(3) Encapsulate on an appropriate encapsulation machine.

EXAMPLE 23

Capsules are prepared by the procedure of Example 22 except that theactive ingredient (item 1) was (AllE)-9-[2-fluoro-6[nonyloxy)phenyl]-3,7-dimethyl-3,4,6,8-nonatetraenoicacid.

EXAMPLE 24

TABLET FORMULATION (Wet granulation)

    ______________________________________                                        Item Ingredients   mg/tablet mg/tablet                                                                             mg/tablet                                ______________________________________                                        1.   (All E)-9-    100         250       500                                       [2-(nonyloxy)                                                                 phenyl]-3,7-                                                                  dimethyl-2,4,                                                                 6,8-nonatetrae-                                                               noic acid                                                                2.   Lactose       98.5        147.5     170                                  3.   Polyvinyl     15          30        40                                        pyrrolidone (PVP)                                                        4.   Modified starch                                                                             15          30        40                                   5.   Corn starch   15          30        40                                   6.   Magnesium     1.5         2.5       5                                         stearate                                                                 Weight of tablet                                                                             245    mg     490  mg   795  mg                                ______________________________________                                    

PROCEDURE:

1. Mix items 1, 2, 4 and 5 in a suitable mixer, granulate with PVP anddissolve in water/alcohol. Dry the granulation. Mill the dry granulationthrough a suitable mill.

2. Add magnesium stearate and compress on a suitable press.

EXAMPLE 25

Tablet are prepared in the same manner as Example 24 except that theactive ingredient (item 1) was (AllE)-9-[2-fluoro-6(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid.

EXAMPLE 26

TABLET FORMULATIONS: (Direct Compression)

    ______________________________________                                        Item Ingredient    mg/tablet mg/tablet                                                                             mg/tablet                                ______________________________________                                        1.   (All E)-9-    15          30        60                                        [2-(nonyloyl)                                                                 phenyl]-3,7-                                                                  dimethyl-2,4,                                                                 6,8-nonatetrae-                                                               noic acid                                                                2.   Lactose       207         192       162                                  3.   Avicel        45          45        45                                   4.   Direct        30          30        30                                        Compression Starch                                                       5.   Magnesium     3           3         3                                    Weight of tablet                                                                             300    mg     300  mg   300  mg                                ______________________________________                                    

PROCEDURE:

1. Mix Item 1 with equal amount of lactose. Mix well.

2. Mix with Item 3, 4, and remaining amount of Item 2. Mix well.

3. Add magnesium stearate and mix for 3 minutes.

4. Compress on a suitable punch.

EXAMPLE 27

CAPSULE FORMULATIONS:

    ______________________________________                                        Item Ingredients   mg/capsule                                                                              mg/capsule                                                                            mg/capsule                               ______________________________________                                        1.   (All E)-(3,7- 15          30        60                                        dimethyl)-9-                                                                  [2[(8-hydroxy-                                                                octyl)oxyl]phenyl]-                                                           2,4,6,8-                                                                      nonatetraenoic]                                                               acid.                                                                    2.   Lactose       239         224       194                                  3.   Starch        30          30        30                                   4.   Talc          15          15        15                                   5.   Magnesium     1           1         1                                    Capsule fill weight                                                                          300    mg     300  mg   300  mg                                ______________________________________                                    

PROCEDURE:

(1) Mix items 1-3 in a suitable mixer.

(2) Add talc and magnesium stearate and mix for a short period of time.

(3) Encapsulate on an appropriate encapsulation machine.

EXAMPLE 28

TABLET FORMULATIONS (Wet granulation)

    ______________________________________                                        Item Ingredient    mg/tablet mg/tablet                                                                             mg/tablet                                ______________________________________                                        1.   (All E)-3,7-  100         250       500                                       dimethyl-9-                                                                   [2,[(octyloxy)                                                                methyl]phenyl]-                                                               2,4,6,8-nona-                                                                 tetraenoic acid                                                          2.   Lactose       98.5        147.5     170                                  3.   Polyvinyl     15          30        40                                        pyrrolidone                                                              4.   Modified starch                                                                             15          30        40                                   5.   Corn starch   15          30        40                                   6.   Magnesium     1.5         2.5       5                                         stearate                                                                 Weight of tablet                                                                             245    mg     490  mg   795  mg                                ______________________________________                                    

PROCEDURE:

1. Mix items 1, 2, 4 and 5 in a suitable mixer, granulate with PVP anddissolve in water/alcohol. Dry the granulation. Mill the dry granulationthrough a suitable mill.

2. Add magnesium stearate and compress on a suitable press.

EXAMPLE 29[[2-Trifluoromethyl-6-(nonyloxy)phenyl]methyl]triphenylphosphoniumbromide

A mixture of α,α,α-trifluoro-m-cresol (51 g), 1-bromononane (70 g),potassium carbonate (100 g) in dimethylformamide was heated at 85° C.for 48 h. Addition of water and hexane gave pure(3-trifluoromethyl)phenyl nonyl ether (89 g): b.p. 115° C. at 0.1 mmHg.This product (89 g) in ether (1.5 L) at -20° C. was mixed withn-butyllithium (1.5M in hexane; 233 mL) and then stirred for 2 h at roomtemperature. This mixture was then cooled to -40°, treated with anexcess of dry dimethylformamide (40 mL) in ether (100 mL), warmed to 0°and then treated with water. Extraction with hexane and chromatographyon silica (5% ether-hexane) gave(2-trifluoromethyl-6-nonyloxy)benzaldehyde (35 g). Reduction of thisproduct with sodiumborohydride is ethanol by the procedure set forth inExample 1 gave (2-trifluoromethyl-6-nonyloxy)benzenemethanol (32 g)after chromatography over silica. This material (31 g) was convertedinto [[2-trifluoromethyl-6(nonyloxy)phenyl]methyl]triphenylphosphoniumbromide by reaction with triphenylphosphine hydrobromide by theprocedure given in Example 1.

EXAMPLE 30(All-E)-9-[2-(Trifluoromethyl)-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid

[[2-trifluoromethyl-6-(nonyloxy)phenyl]methyl]triphenylphosphoniumbromide (97 mmol) in tetrahydrofuran (600 mL) was converted by reactionwith 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester to(All-E)-9-[2-(trifluoromethyl)-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester by the procedure given in Example 3. Purification bychromatography and crystallization from hexane gave the pure ethyl ester(41%). Hydrolysis (5.2 g) as in example 5 gave pure(All-E)-9-[2-(trifluoromethyl)-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid (3 g): mp 135-136 (from ethyl acetate hexane).

EXAMPLE 31(All-E)-9-[2-(hexyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid

[[2-(hexyloxy)phenyl]methyl]triphenylphosphonium bromide, prepared bythe procedure of Example 1 by reacting 2-hydroxybenzaldehyde and1-bromohexane, was converted to(All-E)-9-[2-(hexyloxy)phenyl]-3,7-diethyl-2,4,6,8-nonatetraenoic acid,mp 137°-138° (from ethanol) by the procedure of Example 3.

EXAMPLE 32 [[2-(Nonyloxy)-5-(hydroxy)phenyl]methyl]triphenylphosphoniumbromide

A solution of 4-bromophenol (1 mol) in tetrahydrofuran (500 mL) wasadded to a slurry of sodium hydride (1.17 mol) in dimethylformamide (1.2L) at 25° C. After complete reaction allylchloride (1.32 mol) was addedand after stirring for a further 3 h at 45° the product was isolatedwith water and hexane. Distillation gave allyl-(4-bromophenyl)ether. bp.65°-67° at 0.1 mm (82%). This material was heated at 195° withdimethylanaline for 4 hours and then distilled to yield2-allyl-4-bromophenol (0.81 mol). A solution of this material (0.81 mol)in tetrahydrofuran (200 mL) was added to a mixture of 1-bromononane (0.8mol), sodium hydride (0.92 mol) potassium iodide (1 g) indimethylformamide (1 L) at 25° C. After hydrogen evaluation was completethe mixture was heated at 50° for 14 h, cooled, added to an excess ofwater and extracted with hexane. Distillation furnishednonyl-(2-allyl-4-bromophenyl)ether (256 g): b.p. 147°-156° at 0.1 mm.This material (255 g) in dimethylsulfoxide (1 L) and tetrahydrofuran(0.5 L) was heated at 35°-40° with potassium tert. butoxide (2 g) for 2h and then quenched with acetic acid (5 mL) and water. Isolation of thereaction products with hexane yielded pure1-[2-(nonyloxy)-5-bromo)phenyl]propene (234 g): b.p. 145°-155° at 0.1mm. A solution of the above material (0.56 mol) in tetrahydrofuran (600mL) was converted to the Grignard reagent with magnesium (1 mol) at 55°C. for 3 h. After complete reaction the mixture was cooled to 0° C. andtreated with trimethylborate (0.75 mol) in ether (200 mL). Afterstirring for a further 30 min. at 25° C. the mixture was cooled to 0°and exposed to a mixture of ammonium chloride (B 10%) and hydrogenperoxide (10%, 500 mL) and stirred for a further 1 h at 25° C. Additionof water and hexane gave the crude material after removal of the hexanein vacuo. The crude product was passed through a plug of silica gel toyield para [2-(1-propenyl-4-(nonyloxy)phenyl]phenol (73 g). Acetylationof this material (0.8 g) with acetylchloride and triethylamine indichloromethane gave the[2-(1-propenyl)-4-(nonyloxy)-1-(acetoxy)]benzene (89%). This material(99 g) was dissolved in a mixture of methanol (50 mL) anddichloromethane (1.5 L) and treated with ozone at -40° C. until all thestarting material had been consumed. Dimethylsulfide (50 mL) and water(500 mL) were then added and after vigorous stirring for 30 min. at 25°the organic phase was dried (MgSO₄) and concentrated to yield[2-(nonyloxy)-5-(acetoxy)]benzaldehyde (83 g). Reduction of thismaterial (80 g) with sodium borohydride (6 g) in ethanol (1 L) at 20° C.for 2 h gave the crude [2-(nonyloxy)-5-(acetoxy)]benzenemethanol whichwas immediately exposed to aqueous potassium hydroxide (300 mL, 40%) inethanol (1 L) for 30 min at 60° C. Acidification with aqueous acid (6Molar hydrogen chloride) and extraction with chloroform yielded thecrude product on concentration. Digestion of the residue with hexanegave pure [3-(hydroxymethyl)-4-(nonyloxy)]phenol (63 g) as a solid. Asolution of this material (62 g) in a mixture of acetonitrile (0.5 L)and trihenylphosphine hydrobromide (86 g) was heated at reflux for 14 hand concentrated to dryness at 50° C. to yield[[2-(nonyloxy)-5(hydroxy)phenyl]methyl]triphenylphosphonium bromide as aglass.

EXAMPLE 33(All-E)-9-[5-Hydroxy-2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid

The [[2-(nonyloxy)-5-(hydroxy)phenyl]methyl]triphenylphosphonium bromide(0.23 mol) in tetrahydrofuran (1.5 L) at -70° C. was treated withn-butyllithium (1.6M in hexane; 315 mL) and then treated with ethyl8-formyl-3,7-dimethyl-2,4,6-octatrienoate (59 g) in tetrahydrofuran. Themixture was then warmed to -15° C. acidified with acetic acid andextracted into ether and aqueous methanol (40%). Purification bychromatography over silica gel gave pure(All-E)-9-[5-hydroxy-2(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester. Hydrolysis of this ester (6 g) by the procedure givenin Example 5 gave(All-E)-9-[5-hydroxy-2(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid (3.5 g): mp 170°-173° (from ethylacetate).

EXAMPLE 34(All-E)-9-[2-(nonyloxy)-5-(2,2,2-trifluoroethoxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid

(All-E)-9-[5-hydroxy-2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid ethyl ester (4.4 g) was heated at 90° C. for 72 h with potassiumcarbonate (7 g), 2,2,2-trifluoroethyl-p-toluensulphonate (6 g) indimethylformamide (200 mL). Work up with water and hexane followed bypurification over silica gave the pure ethyl ester (0.75 g). Hydrolysisof this ester (0.9 g) by the procedure of Example 5 gave pure(All-E)-9-[2-(nonyloxy)-5(2,2,2-trifluoroethoxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid (0.6 g) after crystallization from a mixture of tetrahydrofuran andhexane: mp 121° C.

EXAMPLE 35 (Z)-[[2-(1-Decenyl)phenyl]methyl]-triphenylphosphoniumbromide and (E)-[[2(1-Decenyl)phenyl]methyl]triphenylphosphonium bromide

An (E,Z) mixture of 2-(1-decenyl)-1-bromobenzene as prepared in Example16 (1:4) was converted to a (E,Z) mixture of2-(1-decenyl)-1-hydroxymethyl benzene by the procedure of Example 17.This mixture was separated by chromatography on silica gel to yield thepure (E) and (Z) alcohols. Reaction of each of these isomers withtriphenylphosphine hydrobromide as in example 1 gave the correspondingphosphonium salts i.e.(Z)[[2-(1-decenyl)phenyl]methyl]-triphenylphosphonium bromide and(E)[[2-(1-decenyl)phenyl]methyl]triphenylphosphonium bromide.

EXAMPLE 36(All-E)-9-[2-(1-Decenyl)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid

The (E)-[[2-(1-decenyl)phenyl]methyl]-triphenylphosphonium bromide wasconverted into the ethyl ester of(All-E)-9-[2-(decenyl)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acidby the procedure given in Example 1. Hydrolysis with base as in Example1 and crystallization of the crude acid from acetonitrile gave(All-E)-9-[2-(1-decenyl)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid, mp 105-107.

EXAMPLE 37(E,E,E,E,Z)-9-[2-(1-Decenyl)phenyl]-3,7-dimethyl-2,4,6,8Z-nonatetraenoicacid

The title compound was prepared in the same manner as in Example 36employing the (Z)-[[2-(1-decenyl)phenyl]methyl]triphenyl phosphoniumbromide. Hydrolysis of the ethyl ester and crystallization of the crudeacid from ether yielded pure(E,E,E,E,Z)-9-[2-(1-decenyl)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid, mp 103°-105°.

In the following examples, Compound A isAll(E)-9-[2(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid.In the following examples, Compound A was tested by various tests forits anti-inflammatory activity in animal models of inflammation and incertain chronic models for adjuvant arthritis.

In all tests, Compound A and the other retinoids tested concurrentlywere formulated in arachis oil containing 0.05% propylgallate asanti-oxidant. The dose volumes used were 5 ml.kg⁻¹ for rats and 10ml.kg⁻¹ for mice. Controls were dosed with the appropriate volume ofarachis oil vehicle.

EXAMPLE 38 Effect of Compound A on delayed hypersensitivity tomethylated bovine serum albumin (MBSA)

Animals

Male and female MFI mice substrain E33. Initial weight approximately 25gm.

Materials

Methylated bovine serum albumin (MBSA) (Sigma) Freunds complete adjuvant(Difco)

Method

Groups of 10 mice were sensitized (day 0) by injecting intradermally attwo abdominal. sites 0.05 ml. of a water in oil emulsion of MBSA andFreunds complete adjuvant. On day 9 the mice were challenged byinjecting 20 l of a 1% MBSA solution to one paw and 20 l of water intothe contralateral paw. Paw volumes were measured 24 hours later bymercury displacement plethysmography. The mean percentage increase inpaw volume of the MBSA-challenged paw compared with the water challengedpaw was calculated for each treatment group. Dosing with vehicle andretinoid commenced on day 0 and finished on day 9.

Results

The results are given in the following table (Table II)

                  TABLE II                                                        ______________________________________                                        The effects of Compound A in the MBSA                                         delayed hypersensitivity test                                                          Dose               % reduction                                                                            Mean body                                         mg ·                                                                        % increase  (cf. arachis                                                                           weight                                   Treatment                                                                              kg.sup.-1                                                                            paw volume  oil control)                                                                           change (g)                               ______________________________________                                        Arachis         109 ± 11          M 3.8                                    Oil                                  F 0.2                                    Etre-    10     59 ± 9** 46       M -0.8                                   tinate                               F -2.0                                   Com-     10     102 ± 12.sup.ns                                                                         6       M 3.3                                    pound A                              F -0.2                                   Com-     30     50 ± 7***                                                                              54       M 2.8                                    pound A                              F 0.5                                    Com-     100    40 ± 5***                                                                              63       M 3.3                                    pound A                              F -0.2                                   ______________________________________                                    

Each group consisted of 4 male and 6 female mice (separately caged).Drugs were dosed orally at a dose volume of 10 ml.kg⁻¹ (10 doses).

EXAMPLE 39 Effect of Compound A on developing adjuvant arthritis in therat

Animals

AHH/R Female rats (PVG derived with an initial weight range of 110 to140 g. were used.

Materials

Adjuvant for injection. An homogenized suspension of heat killed Mtuberculosis (Human strains C, DT and PN), 5 mg.Ml⁻¹ in liquid paraffinwas prepared.

Method

Rats were randomly split into groups of five and adjuvant arthritis wasinduced by the sub-plantar injection of 0.1 ml of adjuvant suspensioninto the right hind paw of each rat. Test compounds were administered byintubation each morning commencing the day of adjuvant injection. Twogroups of control rats were dosed with the vehicle as was a group ofthree normal rats included for comparative purposes. Dosing was carriedout daily until the end of the test on day 15 except for the firstweekend (days 5 & 6). Treatment groups are shown in Table III andinclude etretinate as standard retinoid.

Measurements of right hind paw volume were made initially and on days 2and 4 after and adjufant injection (primary phase). Right and left hindpaw volume were then measured, on day 8 and every two or three daysuntil the end of the experiment on day 15 (secondary phase). At thistime the mobility of each ankle joint and the incidence and severity ofsecondary lesions on nose, ears, forepaws, left hind paw and tail werealso assessed in terms of degrees of flexion possible and by using anarbitrary scoring system, respectively.

Assessment of results

The time course curves for the injected paws were integrated from days 0to 4 to reflect primary swelling and from days 8 to 15 (secondaryswelling). The secondary swelling in the non-injected paw was integratedsimilarly from days 8 to 15. Calculations were carried out using aspecific computer program which computed mean ± se for each integratedarea. The significance of differences from controls was determined byStudent's t test (2 tailed) and percentage reductions from control areaswere calculated. Percentage improvements in joint mobility andpercentage reductions in lesion score were also determined. In thelatter case the Wilcoxon rank sum test (2 tailed) was used to expressthe difference from the control score using raw data. Mean body weightchange in each group was recorded.

Results

The results are given in the following table (Table III)

                                      TABLE III                                   __________________________________________________________________________    Effect of Compound A and ertretinate on adjuvant arthritis in the rat                       % reduction of paw swelling.sup.1                                                              Lesion.sup.2                                                                        Joint.sup.1                                                                        Body Weight                                Dose   Primary                                                                            Secondary                                                                           Secondary                                                                           Score Mobility                                                                           Change (g)                          Treatment                                                                            mg · kg.sup.-1 p.o.                                                         (right)                                                                            (right)                                                                             (left)                                                                              (% RDN)                                                                             (% INC)                                                                            Days 0-15                                                                           Days 8-15                     __________________________________________________________________________    Normal --     --   --    --    --    --    +13.3***                                                                             +3.7***                     Control                                                                       Adjuvant                                                                             --     --   --    --    --    --   -0.6  -5.5                          Control                                                                       Compound A                                                                           15     -6   30    94*** 72*   66** +2.2  -0.4                                 45     16     51***                                                                             75**  65*   66** +5.4   +1.2*                        Ertretinate                                                                          15      9   30    67*   56*   50   +1.0  -5.0                          __________________________________________________________________________     .sup.1 Statistical analysis by students `t` test (2tailed)                    .sup.2 Statistical analysis by Wilcoxon rank sum test (2tailed)               * =  P < 0.05                                                                 ** = P < 0.02                                                                 *** = P < 0.01                                                           

EXAMPLE 40 Effect of Compound A on established type II collagenarthritis

Animals

Male and female Alderley Park Strain 1 rats.

Materials

Type 2 collagen (prepared from bovine nasal septum cartilage), Freundsincomplete adjuvant (Difco).

Method

Rats were sensitized to type 2 collagen by injecting them intradermallywith 1 ml. of a water in oil emulsion consisting of equal parts of a 1mg.ml⁻¹ solution of type 2 collagen in 0.45M NaCl, 0.02M Tris, pH 7.4and Freunds incomplete adjuvant. Rats developing arthritis wereallocated on day 15 post sensitization to a control arachis oil treatedgroup (6 male, 4 female) or to the Compound A treated group (6 male, 5female). Hind paw volume measurements were taken to ensure evendistribution of rats between groups. An overnight collection of urinewas made on days 15/16 and dosing commenced on day 16. These urinesamples were analyzed for glycosaminoglycans (GAG). Compound A was dosedat 100 mg.kg⁻¹ p.o. On days 19/20 a second overnight collection of urinewas made. These urine samples were analyzed for glycosaminoglycans(GAG). On day 20 a second hind paw measurement was taken. Rats were thenanaesthetised with sodium pentobarbitone, bled, killed and X-rays takenof hind and forepaws. Rats were dosed on days 16-19 inclusive (4 doses).

Results

The results are given in the following Table (Table IV).

                                      TABLE IV                                    __________________________________________________________________________    The effect of Compound A in the type II collagen arthritis test                         Compound A        CONTROL                                                     100 mg · kg.sup.-1                                                                     Arachis Oil                                       DAY Paw Vol                                                                             GAG (μg)                                                                         wt (g)                                                                              Paw Vol                                                                             GAG (μg)                                                                         wt (g)                                      __________________________________________________________________________    16  2.44 ± 0.08                                                                      1586 ± 307                                                                       247 ± 14                                                                         2.48 ± 0.07                                                                      1538 ± 192                                                                       249 ± 19                                 20  2.66 ± 0.06                                                                      634 ± 72                                                                         229 ± 10                                                                         2.46 ± 0.07                                                                       729 ± 134                                                                       258 ± 19                                 __________________________________________________________________________     Comment.                                                                      Both male and female rats lost weight during treatment with Compound A.  

EXAMPLE 41 Effect of Compound A on non-immune inflammation

Animals

Female Alderley Park Strain 1 rats weighing 170-205 g. at the start ofthe experiment were used.

Materials

Lambda-carrageenan. Prepared as a solution in saline and sterilized byautoclaving.

Method

Compound A was administered orally to groups of 8 rats once daily for 10days at doses of 10, 30 and 100 mg.kg⁻¹. Control animals received thevehicle. One hour after the last dose the animals were anesthetised withmethohexitone (Brietal, 50 mg.kg⁻¹) and 0.2 ml of 1% lambda carrageenanwas injected into the pleural cavity. Four hours later the animals werekilled with an overdose of pentobarbitone (Sagatal), the pleural exudatewas collected and the pleural cavity was washed out with 2 ml ofphosphate-buffered saline (PBS-A, Oxoid). The exudate volume wasrecorded and cell counts were determined using an automatic cell counter(Coulter). Differential cell counts were performed on exudate smearsstained with Giemsa stain in order to determine separately the numbersof polymorphonuclear leucocytes (PMN) and mononuclear cells (MN).

Immediately after recovery of the pleural exudates the tibiae of theanimals were excised and their breaking strains were determined.

The body weights of the animals were recorded daily. Statisticalanalyses were performed using Student's two-tailed t test.

Results

The results are given in the following table (Table V). In the followingtable the dose is in mg per kg per day.

                                      TABLE V                                     __________________________________________________________________________    The effects of Compound A on the development of 4 hr carrageenan              pleurisy                                                                                                                       Tibial Breaking                         Exudate  Total Cell                   Strain                                  Volume   Count     Total PMN Total MN (Right + Left)                      Dose     %         %         %        %   Mean %                       Compound                                                                             (p.o.)                                                                            (ml) change                                                                            ×10.sup.6                                                                     change                                                                            ×10.sup.6                                                                     change                                                                            ×10.sup.6                                                                    change                                                                            (kg) change                  __________________________________________________________________________    Control                                                                               5 ml                                                                             1.40 ±                                                                              129.3 ±                                                                              119.1 ±                                                                              10.2 ±                                                                              6.7 ±                     (Arachis oil)                                                                            0.16     3.1       2.9       0.3      0.3                          Compound A                                                                            10 mg                                                                            0.94* ±                                                                         -32.8                                                                             120.8.sup.N.S. ±                                                                  -6.5                                                                             112.4.sup.N.S. ±                                                                  -5.6                                                                             8.4.sup.N.S. ±                                                                  -17.4                                                                             6.5.sup.N.S.                                                                       -3.4                    (Solution) 0.08     7.3       6.7       0.8      0.1                          Compound A                                                                            30 mg                                                                            0.88* ±                                                                         -36.9                                                                             112.1* ±                                                                         -13.3                                                                             104.2* ±                                                                         -12.4                                                                             7.9* ±                                                                          -23.1                                                                             6.8.sup.N.S.                                                                       +1.5                               0.09     6.0       5.6       0.7      0.3                          Compound A                                                                           100 mg                                                                            0.80** ±                                                                        -42.9                                                                             109.1.sup.N.S. ±                                                                 -15.7                                                                             101.6.sup.N.S. ±                                                                 -14.7                                                                             7.5* ±                                                                          -26.7                                                                             6.7.sup.N.S.                                                                       -0.3                               0.08     8.1       7.1       1.1      0.2                          __________________________________________________________________________     N.S., not significant                                                         * = p < 0.05                                                                  ** = p < 0.01 compared with vehicle treated control using Student's           twotailed t test.                                                        

EXAMPLE 42 Effect of Compound A on the impregnated sponge granuloma testin the rat

Animals

AHH/R female rats (PVG derived) with an initial weight range of 120-140g. were used.

Materials

Sponge preparation. Pellets (6.5 mm diameter) were punched fromcellulose sponge cloth ("Wettex") and 0.1 ml. of a suspension containing0.5 mg.ml⁻¹ of heat killed M. tuberculosis (human strains C, DT and PN)in sterile saline was applied to each pellet. The pellets were dried,weighed and autoclaved.

Method

Rats were randomly divided into groups of five and daily dosing withtest compounds was commenced. After the fifth dose the rats wereanaesthetised with Sagatal (45 mg.kg⁻¹ i.p.) the backs were shaved andtwo pellets were implanted subcutaneously (one each side) into each ratthrough a small dorsal midline incision. The incision was closed and therats allowed to recover from the anaesthetic.

Seven days after implantation the rats were killed and the pellets wereremoved, dissected free of extraneous tissue and weighed. Each pelletwas then placed in a 4 ml aliquot of distilled water, chopped with finescissors and sonicated. After centrifugation the Na⁺ and K⁺ content ofthe supernatant was determined by flame photometry. In addition theadrenal and thumus glands from each rat were dissected out and weighedand the lower hind limbs were removed for measurement of tibial bonebreaking strain. Body weights were also recorded throughout the testperiod.

Results

The results are given in the following table (Table VI).

Assessment of results

The mean ± SE for each of the parameters was calculated and differencesfrom the control values were determined by Student's t test (2-tailed).Percentage reductions of granuloma weight, Na⁺ and K⁺ content andpercentage changes of adrenal and thymus, weight and tibial breakingstrain were determined.

                                      TABLE VI                                    __________________________________________________________________________    Effect of Compound A, etretinate and dexamethasone on the impreganted         sponge granuloma test in rats                                                                                 % change in                                                 No. 1.                                                                             % reduction of granuloma tibial                                                                             Body Weight                          Dose  of  Wet           adrenal                                                                             thymus                                                                              breaking                                                                           change                       Treatment                                                                             mg · kg.sup.-1                                                             rats                                                                              weight                                                                             Na+ K+   weight                                                                              weight                                                                              strains                                                                            (g)                          __________________________________________________________________________    Control --    8   --   --  --   --    --    --   +9.6 ± 1.3                Compound A                                                                            15 p.o.                                                                             5   15.1**                                                                             14.5**                                                                            -6.9**                                                                             +17.6**                                                                              -4.4 -4.0  +7.2 ± 0.74                      45 p.o.                                                                             5   10.8 11  0.8  +29.0**                                                                             +14.3  -1.12                                                                             +11.4 ± 0.98              Etretinate                                                                            15 p.o.                                                                             4   2.7  5.9 -3.9 +22.9**                                                                             +15.2 -4.6 +13.3 ± 2.6               Dexamethasone                                                                         0.5 sc                                                                              5    65.5***                                                                           51.2***                                                                           .sup. 75.2***                                                                       -49.5***                                                                            -79***                                                                             -11.5*                                                                             -10.2 ± 1.59              __________________________________________________________________________     * p = < 0.05                                                                  **p = < 0.02                                                                  ***p = < 0.01                                                                 /Comment                                                                      2 control rats and 1 etretinate treated rat died under anaesthesia.      

Animals

Male Lewis rats from Charles River were used for these experiments.

Materials

Heat-killed, dessicated Mycobacteriam butyricum.

Method

Adjuvant arthritis was induced by the injection of 0.1 ml of adjuvant [asuspension of heat-killed, dessicated Mycobacterium butyricum, 0.5%CW/V) in heavy mineral oil containing 0.2% digitonin] into the base ofthe tail. The arthritis was allowed to develop for 21 days and then thevolume of both hind paws were measured using a mercury plethysmograph.The rats were divided into groups of 8 with equal mean paw volumes andthen the rats were treated with Compound A, indomethacin (as a controldrug), or vehicle for 7 days at the end of the treatment period, thevolumes of both hind paws were again measured to assess antiinflammatoryeffects. Body weight changes were also followed and, at the end of theexperiment, plasma was collected for determination of plasma fibrinogen(Exner et. al., Amer. J. Clin. Path, 71: 521-527).

Results:

The results are given in the following Table (Table VII).

                                      TABLE VII                                   __________________________________________________________________________    EFFECT ON THE COURSE OF ESTABLISHED ADJUVANT ARTHRITIS.sup.a                                Change in Paw.sup.c     Change in Body.sup.c                                  Dose Volume   Plasma Fibrinogen                                                                       Weight                                  Group  Treatment.sup.b                                                                      (mg/kg)                                                                            (ml)     (mg/dl)   (g)                                     __________________________________________________________________________    Arthritic(10).sup.b                                                                  Vehicle                                                                              --   +0.53 ± 0.08                                                                        1773 ± 30                                                                            7.5 ± 1.2                            Arthritic(10)                                                                        Compound A                                                                           100  -0.96 ± 0.10*                                                                       874 ± 57*                                                                            5.2 ± 2.1                            Arthritic(10)                                                                        Indomethacin                                                                          1   -1.22 ± 0.15*                                                                        978 ± 100*                                                                          25.6 ± 3.1*                          __________________________________________________________________________     .sup.a Means ± S.E. are reported.                                          .sup.b Drugs were administered once a day for 7 days by intubation            starting on day 22 after induction of the arthritis. Tween 80 was used as     vehicle.                                                                      .sup.c Change in paw volume/body weight equals paw volume body weight on      day 28 minus paw volume/body weight on day 22. Since adjuvant was injecte     into base of tail, change in paw volume is combined value for both hind       paws.                                                                         .sup.d Number of animals per group.                                           *Significantly different from value for vehicletreated arthritic animals      (Student's ttest, p < 0.05).                                             

We claim:
 1. A compound selected from the group of phenyl derivatives ofthe formula: ##STR28## wherein R₁ is hydrogen, lower alkyl, chlorine,fluorine or trifluoromethyl; R₂ is chlorine, trifluoromethyl, loweralkyl, fluorine, hydroxy, loweralkoxy, trifluoromethylloweralkoxy, orhydrogen; R₃ is hydrogen, lower alkyl, chlorine, or fluorine; R₄ is analkyl group having a straight chain length of 4 to 9 carbon atoms; X is##STR29## R₅ is COOR₉ ; and R₇, R₈, R₉, and R₁₀ are hydrogen or loweralkyland pharmaceutically acceptable salts thereof.
 2. The compound ofclaim 1 wherein X is ##STR30##
 3. The compound of claim 2 wherein R₁, R₂and R₃ are hydrogen.
 4. The compound of claim 3 wherein said phenylderivative is3,7-dimethyl-9[2-[(octyloxy)-methyl]phenyl]-2,4,6,8-nonatetraenoic acid.5. The compound of claim 1 wherein X is ##STR31##
 6. The compound ofclaim 5 wherein R₁, R₂ and R₃ are hydrogen.
 7. The compound of claim 6wherein said phenyl derivative is3,7-dimethyl-9-(2-octylaminophenyl)-2,4,6,8-nonatetraenoic acid ethylester.
 8. The compound of claim 6 wherein said phenyl derivative is(all-E)-3,7-dimethyl-9-(2-octylaminophenyl)-2,4,6,8-nonatetraenoic acid.9. The compound of claim 1 wherein X is ##STR32##
 10. The compound ofclaim 9 wherein R₁, R₂ and R₃ are hydrogen.
 11. The compound of claim 10wherein said compound is(all-E)-9-[2-(1-Decenyl)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoicacid.